Mismatched nucleotides may arise from polymerase mis-incorporation errors, recombination between heteroallelic parental chromosomes, or chemical and physical damage of the DNA. MutS homologs (MSH) and MutL homologs (MLH/PMS) are highly conserved proteins and are essential for the MMR excision reaction. In human cells, hMSH2 and hMLH1 are the fundamental components of MMR. The hMSH2 protein forms a heterodimer with hMSH3 or hMSH6 and is required for mismatch/lesion recognition, while the hMLH1 protein forms a heterodimer with hMLH3 or hPMS2 and forms a ternary complex with MSH heterodimers to complete the excision repair reaction. Human cells contain at least 10-times more of the hMSH2-hMSH6/hMLH1-hPMS2 complex, that repairs single nucleotide and small insertiondeletion loop (IDL) mismatches, than the hMSH2-hMSH3/hMLH1-hMLH3 complex that repairs primarily large IDL mismatches. In addition to MMR, the hMSH2-hMSH6/hMLH1-hPMS2 components have been uniquely shown to recognize lesions in DNA and signal cell cycle arrest and apoptosis.
Mutations in the hMSH2, hMSH6, hMLH1 and hPMS2 core MMR genes have been linked to LS/HNPCC. These observations have provided considerable support for the Mutator Hypothesis since defects in the MSH and MLH/PMS genes significantly increase cellular mutation rates that may then drive the evolution of numerous oncogene and tumor suppressor gene mutations found in cancer. One signature of a mutator phenotype is instability of simple repeat sequences or microsatellite DNA (microsatellite instability or MSI). Virtually all LS/HNPCC tumors display MSI that is a result of mutation or inherited epigenetic inactivation of the core MMR genes). The majority of the 10-40% of sporadic CRC, endometrial, ovarian, gastric and urothelial tumors that display MSI are a result of acquired hMLH1 promoter methylation. Approximately 95% of MSI tumors can be at least partially accounted by mutation and/or epigenetic inactivation of the core MMR components. The remaining 5% as well as a significant proportion of the biallelic MMR inactivation mechanism remain poorly understood.
MicroRNAs (miR) are non-coding RNAs that play a role in the post-transcriptional regulation of more than 30% of human genes controlling critical biological processes, including development, cell differentiation, apoptosis and proliferation. Over-expression of miR155 has been observed in CRC, and appears more frequent MSI CRC compared to microsatellite stable (MSS) tumors.
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In spite of considerable research into diseases associated with MMR dysfunction, they remain difficult to diagnose and treat effectively, and the mortality observed in patients indicates that improvements are needed in the diagnosis, treatment and prevention of these diseases.